This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Most dominant mutations that cause Familial Alzheimer's Disease (AD) are found in the two homologous presenilin (PS1, PS2) genes. Little is currently known about the structure and mechanism for the presenilin family of proteases. We plan to solve the crystal structure of a bacterial homolog of presenilin. The structural data is likely to shed light on a number of important questions: (i) How does presenilin cleave peptide bonds that appear to be buried in the membrane? (ii) The disease mutations are found throughout the primary sequence pf PS1 and PS2. How do they all alter the cleavage specificity in favor of the more toxic A[unreadable]42?